sirolimus and Lymphoma--Non-Hodgkin

Results of treatment for patients with non-Hodgkin's lymphomas have significantly improved over the last decade, especially following the discovery that anti-CD20 antibody therapy can significantly change the outlook for patients with both aggressive and indolent lymphomas. Although investigators have previously attempted to prevent relapses by intensifying chemotherapy programs for patients with poor-risk disease, further improvements in treatment will require development of biologic agents that can be added to current programs and exploitation of currently available drugs that can prevent recurrence of these diseases with good tolerability. This review analyzes currently available plans that can be used to maintain responses or "consolidate" initial responses to therapy, programs that may prevent relapse and potentially cure more patients with lymphomas, with a review of current ongoing trials designed along these lines.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Combined Modality Therapy; Disease Progression; Disease-Free Survival; Everolimus; Hematopoietic Stem Cell Transplantation; Humans; Indoles; Lenalidomide; Lymphoma, Non-Hodgkin; Protein-Tyrosine Kinases; Radioimmunotherapy; Randomized Controlled Trials as Topic; Risk Factors; Rituximab; Secondary Prevention; Signal Transduction; Sirolimus; Survival Rate; Thalidomide; Treatment Outcome

The availability of active monoclonal antibodies, either as single agents or in combination with cytotoxic agents, has improved treatment results in non-Hodgkin's lymphoma (NHL). Despite this and the increasing number of available active monoclonal antibodies, alone or conjugated with radioisotopes, not all types of lymphoma are sensitive to these biological agents and often they become resistant because of different molecular mechanisms. New molecular targets in neoplastic cells are emerging and provide the rationale for novel discovery initiatives. In fact, a greater knowledge of the biology of lymphoma and the identification of compounds selectively active against a potential therapeutic pathway have already improved the time to progression and survival time of patients with some subtypes of NHL. The growing list of new drugs provides the exciting prospect of developing disease-specific and even patient-specific therapies. The aim of this review is to identify and discuss non-monoclonal antibody new therapeutic agents in terms of mechanism of action and clinical results. The preclinical and clinical features of proteasome inhibitors, histone deacetylase inhibitors, thalidomide and lenalidomide, mammalian target of rapamycin inhibitors, antisense oligonucleotides, heat shock protein inhibitors, protein kinase C inhibitors, antiangiogenic agents, and new cytotoxics are reviewed.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Boronic Acids; Bortezomib; Clinical Trials as Topic; Histone Deacetylase Inhibitors; HSP90 Heat-Shock Proteins; Humans; Lymphoma, Non-Hodgkin; Oligonucleotides, Antisense; Proteasome Inhibitors; Protein Kinase C; Pyrazines; Sirolimus

Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR), has anti-tumor activity in patients with relapsed or refractory mantle cell lymphoma (MCL) and other mature lymphoid neoplasms. mTOR is an intracellular kinase that controls the mRNA translation of many proteins (eg, cyclin D1) that can act as oncogenes and contribute to lymphomagenesis. Characterized by overexpression of cyclin D1, MCL was identified as a disease that might be susceptible to mTOR inhibition. When single-agent temsirolimus was explored in two phase II studies for treatment of patients with relapsed or refractory MCL, it demonstrated anti-tumor activity, with overall response rates of 38% and 41%. Subsequently, a three-arm, randomized phase III trial was conducted to compare two dosing regimens of temsirolimus with investigator's choice of therapy for heavily pretreated patients with relapsed or refractory MCL (N = 162; randomized 1:1:1). Once-weekly intravenous temsirolimus 175 mg for 3 weeks followed by 75 mg once weekly (175/75) significantly improved progression-free survival (hazard ratio = 0.44; P = .0009) versus investigator's choice therapy. Median progression-free survival durations were 4.8 and 1.9 months, respectively. The objective response rates were 22% in the 175/75 group and 2% in the investigator's choice group (P = .0019). For patients receiving temsirolimus, the most frequent grade 3 or 4 adverse events were thrombocytopenia, anemia, neutropenia, and asthenia. The results of this trial established a recommended clinical dose for temsirolimus monotherapy in patients with relapsed or refractory MCL and validated the importance of mTOR in the pathogenesis of advanced MCL. Objective responses also have been reported for other mature B-cell neoplasms (eg, diffuse large B-cell lymphoma or follicular lymphoma) in the phase II setting. Temsirolimus as monotherapy or in combination with other active agents warrants further investigation for treatment of MCL and other non-Hodgkin lymphomas.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Humans; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Models, Biological; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

The mammalian target of rapamycin (mTOR) is a large and highly conserved kinase that integrates growth factor stimulation, energy and nutrient availability to modulate translation of proteins responsible for cellular growth and proliferation. Its importance in malignant cells provides strong rationale for the development of mTOR inhibitors (mTORi) in a broad variety of solid tumors and hematological malignancies. However several questions regarding mTOR biology and its interaction with pharmacological inhibitors remain unanswered and are relevant for further development of this novel family of cancer drugs. Nevertheless, mTORi have demonstrated activity in lymphoma cells either alone or in combination with cytotoxic agents. The most promising results have been seen in mantle cell lymphoma (MCL), likely because of its dependence on Cyclin D, the translation of which is largely regulated by mTOR activity. The currently knowledge of mTOR biology will here be reviewed along with the status of clinical development of mTORi in non-Hodgkin's lymphomas.

Topics: Antibiotics, Antineoplastic; Cyclin D1; Humans; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Protein Kinase Inhibitors; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

The non-Hodgkin lymphomas (NHL) are characterized by initial responsiveness to a variety of chemotherapeutic regimens. Nevertheless, most patients progress and die from their disease. A number of new agents with unique mechanisms of action are in clinical development. Agents that are currently considered to be the most promising include those that induce apoptosis; those that interfere with cell cycling, tumor-associated angiogenesis, farnesylation of the Ras gene, and histone deacetylase; and those that inhibit the proteasome, among others. Increasing insights into the differences between tumors and among patients will lead to more individualized therapeutic strategies using agents directed at specific genetic and immunologic targets. More rapid accrual to high-quality clinical studies will facilitate dissemination of new agents to patients and lead to an increased cure rate for NHL.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antineoplastic Agents; Arsenicals; Cisplatin; Cyclins; Histone Deacetylase Inhibitors; Humans; Lymphoma, Non-Hodgkin; Protein Kinase Inhibitors; Sirolimus; Topoisomerase I Inhibitors

In this phase II study (NCT00942747), temsirolimus was tested in patients with relapsed or refractory primary CNS lymphoma (PCNSL).. Immunocompetent adults with histologically confirmed PCNSL after experiencing high-dose methotrexate-based chemotherapy failure who were not eligible for or had experienced high-dose chemotherapy with autologous stem-cell transplant failure were included. The first cohort (n = 6) received 25 mg temsirolimus intravenously once per week. All consecutive patients received 75 mg intravenously once per week.. Thirty-seven eligible patients (median age, 70 years) were included whose median time since their last treatment was 3.9 months (range, 0.1 to 14.6 months). Complete response was seen in five patients (13.5%), complete response unconfirmed in three (8%), and partial response in 12 (32.4%) for an overall response rate of 54%. Median progression-free survival was 2.1 months (95% CI, 1.1 to 3.0 months). The most frequent Common Toxicity Criteria ≥ 3° adverse event was hyperglycemia in 11 (29.7%) patients, thrombocytopenia in eight (21.6%), infection in seven (19%), anemia in four (10.8%), and rash in three (8.1%). Fourteen blood/CSF pairs were collected in nine patients (10 pairs in five patients in the 25-mg cohort and four pairs in four patients in the 75-mg cohort). The mean maximum blood concentration was 292 ng/mL for temsirolimus and 37.2 ng/mL for its metabolite sirolimus in the 25-mg cohort and 484 ng/mL and 91.1 ng/mL, respectively, in the 75-mg cohort. Temsirolimus CSF concentration was 2 ng/mL in one patient in the 75-mg cohort; in all others, no drug was found in their CSF.. Single-agent temsirolimus at a weekly dose of 75 mg was found to be active in relapsed/refractory patients with PCNSL; however, responses were usually short lived.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Central Nervous System Neoplasms; Female; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Sirolimus

Proteasome inhibitors and mammalian target of rapamycin inhibitors each have activity in various B-cell malignancies and affect distinct cellular pathways. Their combination has demonstrated synergy in vitro and in mouse models.. The authors conducted a single-arm, phase 2 trial of combined temsirolimus and bortezomib in patients with relapsed and refractory B-cell non-Hodgkin lymphoma (NHL) using a dosing scheme that was previously tested in multiple myeloma. The patients received bortezomib and temsirolimus weekly on days 1, 8, 15, and 22 of a 35-day cycle.. Of 39 patients who received treatment, 3 achieved a complete response (7.7%; 95% confidence interval [CI], 1.6%-21%), and 9 had a partial response (PR) (23%; 95% CI, 11%-39%). Thus, the overall response rate (12 of 39 patients) was 31% (95% CI, 17%-48%), and the median progression-free survival was 4.7 months (95% CI, 2.1-7.8 months; 2 months for patients with diffuse large B-cell lymphoma [n = 18], 7.5 months for those with mantle cell lymphoma [n = 7], and 16.5 months for those with follicular lymphoma [n = 9]). Two extensively treated patients with diffuse large B-cell lymphoma achieved a complete response. There were no unexpected toxicities from the combination.. The current results demonstrate that the combination of a mammalian target of rapamycin inhibitor and a proteasome inhibitor is safe and has activity in patients with heavily pretreated B-cell NHL. Further studies with this combination are warranted in specific subtypes of NHL.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Disease-Free Survival; Female; Humans; Incidence; Lymphoma, Non-Hodgkin; Male; Sirolimus; Wisconsin

To evaluate the safety and efficacy of panobinostat plus everolimus in patients with relapsed Hodgkin and non-Hodgkin lymphoma. The concept was supported by the single-agent clinical activity of histone deacetylase inhibitors and mTOR inhibitors, and on the in vitro mechanism-based synergistic antiproliferative activity.. This was a phase I study in patients with relapsed or refractory Hodgkin and non-Hodgkin lymphoma using panobinostat orally on Monday/Wednesday/Friday and everolimus orally daily. Toxicity and responses were assessed in dose-escalation cohort followed by expansion cohort at maximum-tolerated dose. Exploratory analysis of serum cytokine levels was performed.. Thirty patients were enrolled onto four dose levels. The dose-limiting toxicity was thrombocytopenia. The maximal tolerated dose was panobinostat 20 mg and everolimus 10 mg. Grade 3/4 toxicity included thrombocytopenia (64%), neutropenia (47%), anemia (20%), infection (10%), fatigue (7%), and dyspnea (7%). A total of 10 patients (33%; indolent lymphoma, T-cell lymphoma, mantle cell lymphoma, and Hodgkin lymphoma) achieved objective responses. In patients with Hodgkin lymphoma (n = 14), the overall response rate was 43% with complete response rate of 15%. In patients with Hodgkin lymphoma, multiple serum cytokine levels decreased significantly after treatment with this combination therapy. Of note, clinical responses were associated with a decrease in serum interleukin-5 levels (day 8, P = 0.013, and day 15, P = 0.021).. Our data suggest that the combination therapy is active but with significant thrombocytopenia. Future studies should explore alternate scheduling and different compounds that target the same pathways to improve the tolerability of this novel combination.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Everolimus; Female; Histone Deacetylase Inhibitors; Hodgkin Disease; Humans; Hydroxamic Acids; Indoles; Interleukin-5; Lymphoma, Non-Hodgkin; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Recurrence, Local; Panobinostat; Sirolimus; TOR Serine-Threonine Kinases

Reduced-intensity conditioning (RIC) allo-SCT is a potentially curative treatment approach for patients with relapsed Hodgkin's or non-Hodgkin's lymphoma. In the present study, 37 patients underwent RIC allo-SCT after induction treatment with EPOCH-F(R) using a novel form of dual-agent immunosuppression for GVHD prophylaxis with CsA and sirolimus. With a median follow-up of 28 months among survivors, the probability for OS at 3 and 5 years was 56%. Treatment-related mortality was 16% at day +100 and 30% after 1 year of transplant. Acute GVHD grades II-IV developed in 38% of patients, suggesting that the regimen consisting of CsA and an ultra-short course of sirolimus is effective in the prevention of acute GVHD.

Topics: Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Etoposide; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Immunosuppressive Agents; Lymphoma, Non-Hodgkin; Male; Middle Aged; Prednisolone; Rituximab; Sirolimus; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Vincristine; Young Adult

The phosphatidylinositol 3-kinase signal transduction pathway members are often activated in tumor samples from patients with non-Hodgkin's lymphoma (NHL). Everolimus is an oral agent that targets the raptor mammalian target of rapamycin (mTORC1). The goal of this trial was to learn the antitumor activity and toxicity of single-agent everolimus in patients with relapsed/refractory aggressive NHL. Patients received everolimus 10 mg PO daily. Response was assessed after two and six cycles, and then every three cycles until progression. A total of 77 patients with a median age of 70 years were enrolled. Patients had received a median of three previous therapies and 32% had undergone previous transplant. The overall response rate (ORR) was 30% (95% confidence interval: 20-41%), with 20 patients achieving a partial remission and 3 a complete remission unconfirmed. The ORR in diffuse large B cell was 30% (14/47), 32% (6/19) in mantle cell and 38% (3/8) in follicular grade 3. The median duration of response was 5.7 months. Grade 3 or 4 anemia, neutropenia and thrombocytopenia occurred in 14, 18 and 38% of patients, respectively. Everolimus has single-agent activity in relapsed/refractory aggressive NHL and provides proof-of-concept that targeting the mTOR pathway is clinically relevant.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Everolimus; Female; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Protein Kinase Inhibitors; Remission Induction; Salvage Therapy; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Despite high initial remission rates, most lymphomas relapse and require further therapy. The mammalian target of rapamycin (mTOR) pathway is a validated target in mantle cell lymphoma, but has not been extensively evaluated in other lymphomas.. We performed a phase II trial of single-agent temsirolimus 25-mg weekly in patients with relapsed aggressive and indolent lymphomas. The primary objective was overall and complete response rate. Patients were stratified by histology: group A (diffuse large B-cell lymphoma, transformed follicular lymphoma), group B (follicular lymphoma), and group C (chronic lymphocytic leukemia/small lymphocytic lymphoma, and other indolent lymphomas).. Eighty-nine patients were treated, with outcome strongly dependent on histology. Group A had an overall and complete response rate of 28.1% and 12.5%, respectively, and median progression-free survival (PFS) of 2.6 months and median overall survival (OS) of 7.2 months. Group B had overall and complete response rates of 53.8% and 25.6%, respectively, and median PFS of 12.7 months; median OS has not yet been reached. Group C had a partial response rate of 11% with no complete responders. Toxicity was mainly mild and/or reversible myelosuppression and mucositis; however, four patients developed pneumonitis.. Single-agent temsirolimus has significant activity in both diffuse large B-cell lymphoma and follicular lymphoma, although the durability of responses and PFS are longer for patients with follicular lymphoma. This is the first report of substantial activity of temsirolimus in lymphomas other than mantle cell lymphoma, and supports further evaluation of mTOR as a target in these diseases.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bone Marrow; Chicago; Disease-Free Survival; Female; Humans; Intracellular Signaling Peptides and Proteins; Kaplan-Meier Estimate; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Mucositis; Pneumonia; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Remission Induction; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Phase I study was conducted to evaluate the safety, pharmacokinetics (PK) and efficacy of the oral mammalian target of rapamycin inhibitor, everolimus (RAD001), in patients with relapsed or refractory non-Hodgkin lymphoma (NHL). Patients received everolimus 5 or 10 mg orally once daily. Dose escalation was based on the safety assessment and the probability of dose-limiting toxicities (DLTs) using a Bayesian logistic model. DLTs were evaluated in six patients at each dose level during the initial 28 days of study treatment. A total of 13 patients were enrolled; 5 mg (seven) and 10 mg (six). No DLTs were observed at either dose level. Frequently observed potentially drug-related adverse events included leukopenia (8/13), thrombocytopenia (8/13), elevated hepatic transaminase (9/13), stomatitis (7/13), anemia (6/13), and nasopharyngitis (6/13). All adverse events were reversible. Non-infectious pneumonitis (grade 1) in one patient resolved following discontinuation of everolimus. Two patients with diffuse large B cell lymphoma and two patients with follicular lymphomas achieved objective responses with an overall response rate of 31% (4/13). The pharmacokinetic profiles were not different from those in non-Japanese patients. Everolimus was well tolerated at doses up to 10 mg/day and showed potential efficacy in relapsed or refractory NHL, warranting further investigation.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Everolimus; Female; Humans; Immunosuppressive Agents; Japan; Lymphoma, Non-Hodgkin; Male; Middle Aged; Recurrence; Sirolimus; TOR Serine-Threonine Kinases

Temsirolimus, a specific inhibitor of the mammalian target of rapamycin kinase, has shown clinical activity in mantle cell lymphoma (MCL). We evaluated two dose regimens of temsirolimus in comparison with investigator's choice single-agent therapy in relapsed or refractory disease.. In this multicenter, open-label, phase III study, 162 patients with relapsed or refractory MCL were randomly assigned (1:1:1) to receive one of two temsirolimus regimens: 175 mg weekly for 3 weeks followed by either 75 mg (175/75-mg) or 25 mg (175/25-mg) weekly, or investigator's choice therapy from prospectively approved options. The primary end point was progression-free survival (PFS) by independent assessment.. Median PFS was 4.8, 3.4, and 1.9 months for the temsirolimus 175/75-mg, 175/25-mg, and investigator's choice groups, respectively. Patients treated with temsirolimus 175/75-mg had significantly longer PFS than those treated with investigator's choice therapy (P = .0009; hazard ratio = 0.44); those treated with temsirolimus 175/25-mg showed a trend toward longer PFS (P = .0618; hazard ratio = 0.65). Objective response rate was significantly higher in the 175/75-mg group (22%) compared with the investigator's choice group (2%; P = .0019). Median overall survival for the temsirolimus 175/75-mg group and the investigator's choice group was 12.8 months and 9.7 months, respectively (P = .3519). The most frequent grade 3 or 4 adverse events in the temsirolimus groups were thrombocytopenia, anemia, neutropenia, and asthenia.. Temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly significantly improved PFS and objective response rate compared with investigator's choice therapy in patients with relapsed or refractory MCL.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Disease-Free Survival; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Humans; Kaplan-Meier Estimate; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Neoplasm Staging; Prospective Studies; Protein Kinase Inhibitors; Protein Kinases; Recurrence; Sirolimus; TOR Serine-Threonine Kinases

Topics: Adolescent; Adult; Aged; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Male; Middle Aged; Multiple Myeloma; Remission Induction; Risk; Sirolimus; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Triazoles; Young Adult

TGF-β1 (transforming growth factor beta 1) is a negative regulator of lymphocytes, inhibiting proliferation and switching on the apoptotic program in normal lymphoid cells. Lymphoma cells often lose their sensitivity to proapoptotic/anti-proliferative regulators such as TGF-β1. Rapamycin can influence both mTOR (mammalian target of rapamycin) and TGF-β signaling, and through these pathways it is able to enhance TGF-β induced anti-proliferative and apoptotic responses. In the present work we investigated the effect of rapamycin and TGF-β1 combination on cell growth and on TGF-β and mTOR signalling events in lymphoma cells. Rapamycin, an inhibitor of mTORC1 (mTOR complex 1) did not elicit apoptosis in lymphoma cells; however, the combination of rapamycin with exogenous TGF-β1 induced apoptosis and restored TGF-β1 dependent apoptotic machinery in several lymphoma cell lines with reduced TGF-β sensitivity in vitro. In parallel, the phosphorylation of p70 ribosomal S6 kinase (p70S6K) and ribosomal S6 protein, targets of mTORC1, was completely eliminated. Knockdown of Smad signalling by Smad4 siRNA had no influence on apoptosis induced by the rapamycin+TGF-β1, suggesting that this effect is independent of Smad signalling. However, apoptosis induction was dependent on early protein phosphatase 2A (PP2A) activity, and in part on caspases. Rapamycin+TGF-β1 induced apoptosis was not completely eliminated by a caspase inhibitor. These results suggest that high mTOR activity contributes to TGF-β resistance and lowering mTORC1 kinase activity may provide a tool in high grade B-cell lymphoma therapy by restoring the sensitivity to normally available regulators such as TGF-β1.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Humans; Lymphoma, Non-Hodgkin; Mice, SCID; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Signal Transduction; Sirolimus; Smad4 Protein; Transforming Growth Factor beta1; Xenograft Model Antitumor Assays

Autophagy is a critical mechanism in both cancer therapy resistance and tumor suppression. Monoclonal antibodies have been documented to kill tumor cells via apoptosis, antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In this study, we report for the first time that chLym-1, a chimeric anti-human HLA-DR monoclonal antibody, induces autophagy in Raji Non-Hodgkin's Lymphoma (NHL) cells. Interestingly, inhibition of autophagy by pharmacological inhibitors (3-methyladenine and NH4Cl) or genetic approaches (siRNA targeting Atg5) suppresses chLym-1-induced growth inhibition, apoptosis, ADCC and CDC in Raji cells, while induction of autophagy could accelerate cytotoxic effects of chLym-1 on Raji cells. Furthermore, chLym-1-induced autophagy can mediate apoptosis through Caspase 9 activation, demonstrating the tumor-suppressing role of autophagy in antilymphoma effects of chLym-1. Moreover, chLym-1 can activate several upstream signaling pathways of autophagy including Akt/mTOR and extracellular signal-regulated kinase 1/2 (Erk1/2). These results elucidate the critical role of autophagy in cytotoxicity of chLym-1 antibody and suggest a potential therapeutic strategy of NHL therapy by monoclonal antibody chLym-1 in combination with autophagy inducer.

Topics: Ammonium Chloride; Antibodies, Monoclonal; Antineoplastic Agents; Apoptosis; Autophagy; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Inhibitory Concentration 50; Lymphoma, Non-Hodgkin; MAP Kinase Signaling System; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Sirolimus

Non-Hodgkin lymphoma (NHL) represents a heterogenous group of neoplasias originating from lymphoid cells. Increased angiogenesis and expression of Vascular Endothelial Growth Factor (VEGF) and its receptors (VEGFR) have been found to be associated with NHL disease progression. Increase in VEGF and other cytokines stimulate signaling cascades, including the Ras/Raf/Mek/Erk pathway, resulting in increased proliferation and decreased apoptosis. Here, we report the in vitro antilymphoma activity of sorafenib, an inhibitor of VEGFR and Raf kinase. Sorafenib induced potent cytotoxicity in NHL cell lines and patient samples. This induction of cytotoxicity was associated with a corresponding increase in apoptotic cell death. Mechanism of action of sorafenib was investigated in follicular (DoHH2) and Burkitt lymphoma (Raji) cell lines. pStat3, pAkt, Mcl1, and Xiap were downregulated in both cell lines, whereas pErk decreased in Raji but not in DoHH2 cells following sorafenib treatment. IL6 was unable to prevent sorafenib induced repression of pStat3, pAkt, Mcl1, and Bcl-Xl. Sorafenib in combination with an mTORC1 inhibitor rapamycin demonstrated synergy in inducing cytotoxicity in NHL cells. Sorafenib/rapamycin combination resulted in downregulation of pAkt, pmTOR, p-p70S6K, p4EBP1, pGSK3β, Mcl1, and Bcl-Xl. On the basis of our results, a clinical trial is underway using sorafenib with everolimus in NHL patients.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Apoptosis; Benzenesulfonates; Cell Line, Tumor; Drug Screening Assays, Antitumor; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; In Vitro Techniques; Interleukin-6; Lymphoma, Non-Hodgkin; Neoplasm Proteins; Niacinamide; Phenylurea Compounds; Pyridines; raf Kinases; Receptors, Vascular Endothelial Growth Factor; Sirolimus; Sorafenib; TOR Serine-Threonine Kinases

Topics: Aged; Angiomyolipoma; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Lymphoma, Non-Hodgkin; Nephrectomy; Prednisone; Sarcoma, Kaposi; Sirolimus; Splenectomy; Tomography, X-Ray Computed; Vincristine

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Drug Resistance, Neoplasm; Etoposide; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Prednisolone; Remission Induction; Sirolimus; Tongue Neoplasms; Treatment Failure; Treatment Outcome; Vincristine

Single-agent mammalian target of rapamycin complex 1 (mTORC1) inhibitors have recently been reported as effective salvage treatment in non-Hodgkin lymphoma (NHL). The combined effect of mTORC1 inhibitor, RAD001, with chemotherapeutic agents used for relapsed or refractory NHL was examined. Synergistic interactions were observed for RAD001 plus gemcitabine or paclitaxel in six NHL cell lines; enhanced gemcitabine- and paclitaxel-induced caspase-dependent apoptosis associated with down-regulation of mTOR signaling was detected. Synergistic interactions were also observed with RAD001 plus gemcitabine and paclitaxel. In conclusion, synergistic cytotoxicity was observed with RAD001 plus gemcitabine and paclitaxel in NHL cells. Combination therapy with these three drugs should be examined in patients with refractory or relapsed NHL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Caspases; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Activation; Everolimus; Gemcitabine; Humans; Immunosuppressive Agents; Jurkat Cells; Lymphoma, Non-Hodgkin; Myeloid Cell Leukemia Sequence 1 Protein; Paclitaxel; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Topics: Everolimus; Humans; Immunosuppressive Agents; Killer Cells, Natural; Lymphoma, Extranodal NK-T-Cell; Lymphoma, Non-Hodgkin; Lymphoma, T-Cell; Prognosis; Sirolimus; Stem Cell Transplantation

Diffuse large B-cell lymphoma (DLBCL) is a common lymphoma entity. Although a significant amount of DLBCL patients can be cured with modern chemotherapeutic regimens, a substantial proportion of patients die because of progressive disease. Therefore, new therapeutic strategies are clearly needed. Inhibitors of mTOR [mammalian target of rapamycin (Rap)] represent a new class of antiproliferative drugs with applications as immunosuppressive and anticancer agents. Extensive safety data exist on the mTOR inhibitor RAD001, which is already approved as an immunosuppressant in organ transplant recipients. Rap and RAD001 inhibited cell cycle progression in DLBCL cells by inducing a G1 arrest without inducing apoptosis. Phosphorylation of the main targets of mTOR, p70 s6 kinase and 4-EBP-1 was reduced in cells cultured in the presence of RAD001. Cell cycle arrest was accompanied by reduced phosphorylation of the retinoblastoma protein (RB) as well as reduced expression of cyclin D3 and A in all cell lines. Although the effect of the chemotherapeutic agent vincristine (vin) was not enhanced by RAD001, rituximab-induced cytotoxicity was augmented in the rituximab-sensitive cell lines. mTOR inhibition is a promising therapeutic strategy in DLBCL by inducing a G1 arrest and augments rituximab-induced cytotoxicity. Therefore, combination of these drugs might be an interesting new therapeutic approach in DLBCL patients.

Topics: Adaptor Proteins, Signal Transducing; Annexin A5; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Electrophoretic Mobility Shift Assay; Everolimus; Flow Cytometry; G1 Phase; Humans; Immunosuppressive Agents; In Situ Nick-End Labeling; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Non-Hodgkin; Oncogene Protein v-akt; Phosphoproteins; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; PTEN Phosphohydrolase; Retinoblastoma Protein; Ribosomal Protein S6 Kinases, 70-kDa; Rituximab; Sirolimus; TOR Serine-Threonine Kinases

Topics: Animals; Antineoplastic Agents; Clinical Trials, Phase II as Topic; Drug Evaluation, Preclinical; Epstein-Barr Virus Infections; Humans; Immunocompromised Host; Immunosuppressive Agents; Lymphoma, Non-Hodgkin; Mice; Neoplasm Metastasis; Postoperative Complications; Sirolimus; Transplantation Immunology; Tumor Virus Infections; Virus Activation

Lymphosarcoma P1798 cells undergo growth arrest when exponentially growing cultures are exposed to 1 micrograms/ml of Rapamycin (Rapa). This growth arrest is accompanied by inhibition of RNA biosynthesis as measured by incorporation of 3H-uridine into the newly synthesized RNA. Approximately 50% inhibition of 3H-uridine incorporation was observed, upon exposure of P1798 cells to 1 microgram/ml Rapa for 24 h. Run-on transcription experiments using nuclei from Rapa-treated cells indicated a dose-dependent inhibition of transcription or rRNA genes. Cells were relieved from this inhibition of transcription when Rapa was removed from the medium. Under similar conditions, transcriptions of U3 snRNA genes remained unaffected. Cytoplasmic extracts prepared from P1798 cells treated with 1 microgram/ml Rapa for 24 h failed to support transcription from cloned mouse rRNA promoter. This treatment does not affect the RNA polymerase I activity of P1798 cells. Addition of a highly purified murine transcription initiation factor specific for RNA polymerase I reconstitutes the extracts from Rapa-treated P1798 cells. Our data indicate that this new immunosuppressive agent modulates transcription of rRNA genes via regulation of specific transcription factor function.

Topics: Animals; Cyclosporine; DNA; Immunosuppressive Agents; Lymphoma, Non-Hodgkin; Mice; Polyenes; RNA; RNA Polymerase I; RNA, Ribosomal; Sirolimus; Transcription Factors; Transcription, Genetic; Tumor Cells, Cultured